DE2165276A1 - 8-Benzofurylmethyl-1,3,8-triazaspiro (4,5) decane - Google Patents

Description

CIBA-GEIGY AG, BASEL (SWITZERLAND)

Case 4-7338 / SU 572 / I + 2 GERMANY

8-Benzofurylmethyl-1,3,8-trlazaspiro (4,5) decane.

The present invention relates to

8- [1- (2,3-Dihydro-2-benzofuryl) alkyl] -1,3,8-triazaspiro (4,5) decane of the general formula I.

. R.

(D,

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wherein Ph is a 1,2-phenylene radical, any of the R, Rp and R, represent hydrogen or lower alkyl . stands, each of the radicals alk, and alkp lower alkylene means which separates the nitrogen atom from the spiro carbon atom by 2 ring carbon atoms, R ^ for Is hydrogen, an aliphatic, araliphatic or aromatic radical, R ^. two hydrogen atoms, hydrogen and is lower alkyl or oxo, and Rg is hydrogen, lower alkyl or lower hydroxyalkyl stands, their acyl derivatives, N-oxides, quaternary ammonium compounds and salts.

In formula I, the 1,2-phenylene radical Ph is unsubstituted or substituted by one or more than one, preferably one or two, identical or different substituents. Substituents are, for example, lower alkyl, such as methyl, ethyl, n- or i-propyl or butyl; free, etherified or esterified Hydroxy, mercapto or lower hydroxyalkyl, preferably α-hydroxyalkyl, e.g. lower alkoxy, alkylenedioxy, alkylthio, Halogen, lower (hydroxy, alkoxy, mono-, di- or trihalo) -alkyl ,. such as methoxy, ethoxy, rir or i-propoxy or butoxy; Methylenedioxy; Methyl or ethylthio; Fluorine, chlorine or bromine; (Hydroxy, methoxy, chlorine or trifluoro) methyl, 1- or 2- (hydroxy, methoxy or chlorine) ethyl or 1-hydroxy-2-methylpropyl; Nitro, amino or di-lower alkylamino, such as dimethylamino or diethylamino; or acyl, e.g. lower

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alkanoyl, lower alkylsulphinyl or lower alkylsulphonyl, such as acetyl, propionyl or butyryl; Methyl or ethylsulfinyl or methyl or ethylsulfonyl.

The term “lower” defines in connection with the organic radicals mentioned above or below or compounds, preferably those with a maximum of 7 * 4 carbon atoms,

Preferred Ph radicals are 1,2-phenylene, (lower alkyl) -1,2-phenylene, (hydroxy) -1,2-phenylene, mono- or di- (lower alkoxy) -1,2-phenylene, (lower alkylenedioxy) -1,2-phenylene, (Lower alkylthio) -1,2-phenylene, (halogen) -1,2-phenylene, (lower a-hydroxy-alkyl) -l, 2-phenylene, (trifluoromethyl) -1,2-phenylene, (Nitro) -1,2-phenylene, (amino) -1,2-phenylene, (Di-lower alkylamino) -l, 2-phenylene, (lower alkanoyl) - !, 2-phenylene, (Lower alkylsulfinyl) -1, 2-phenylene or (lower alkylsulfonyl) -1,2-phenylene.

Each of the symbols R- ,, Rp, R ^ ,, Rt- and R, - means preferably hydrogen, but also lower alkyl, e.g. an above-mentioned lower alkyl radical, in particular methyl, or Rj- hydrogen and lower alkyl, e.g., methyl.

The lower alkylene radicals alk and alk ₂ are preferably 1,2-ethylene, but also 1,2-propylene, 1,2- or 2,3-butylene.

An aliphatic radical R ₂ is, for example, lower alkyl, such as an above-mentioned lower alkyl radical, lower alkenyl

209831/1 151.

or lower alkynyl, such as allyl, methallyl, 2- or 3-butenyl; Propargyl, 2- or 3-butynyl; lower cycloalkyl, Cycloalkenyl, cycloalkyl-lower alkyl or cycloalkenyl-lower alkyl, such as cyclopropyl, cyclopentyl, cyclohexyl; 2-cyclopentenyl or cyclohexenyl; Cyclopropylmethyl, cyclobutylmethyl or 2-cyclopentylethyl; Cyclopent-2-enyl-methyl or cyclohex-3-enyl-methyl.

An araliphatic or aromatic radical PL is preferably one of the formula H-Ph-C Hp, wherein Ph has the meaning given above and η for 0 to 4, preferably 0 or 1.

A lower hydroxyalkyl group IL- is preferred Hydroxymethyl, 1- or 2-hydroxy-ethyl, but also 1-, 2- or 3-hydroxypropyl or -butyl.

The acyl derivatives are preferably derived on the one hand from compounds of the formula I in which PU and / or FL is hydrogen, or Ph or Rg contains hydroxy, mercapto or amino, on the other hand from lower aliphatic, araliphatic or aromatic carboxylic acids, for example from those of the formulas CH ₂ COOH or HPh - C _n H _3n - COOH, in which η and Ph have the meanings given above. Acyl derivatives are, for example, acetyl, propionyl, pivaloyl, phenylacetyl or benzoyl derivatives.

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The N-Oxides and the Quaternary Ammonium Compounds are derived from compounds of the formula I in which the two radicals R ^ and Rg are different from hydrogen and Ph is different from (amino) -l, 2-phenylene, while the quaternary ammonium compounds are lower alkyl halides, sulfates or sulfonates, e.g. lower alkyl ammonium chlorides, iodides, sulfates, methane or p-toluenesulfonates are.

Salts of compounds of formula I are preferably therapeutically useful acid addition salts, e.g. those of the below-mentioned inorganic and organic acids.

The compounds of the present invention show valuable pharmacological properties, especially depressive ones Effects on the central nervous system and analgesic effects. These can be tested on animals, preferably on mammals, e.g. rats, mice, rabbits, cats, Dogs and especially monkeys. The compounds of the invention can be administered enterally or parenterally e.g. orally, subcutaneously, intraperitoneally or intravenously, such as in the form of gelatin capsules, mixed with corn starch or as aqueous solutions or suspensions. The oral dose is in lower animals, e.g. mice or Cats, in a range of about between 0.1 and 200 mg / kg / day, preferably about 1 and

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50 mg / kg / day and in higher animals such as monkeys or dogs, between about 0.1 and 10 mg / kg / day, preferably between 0.3 and 2.5 mg / kg / day. The new compounds induce, for example, a calming effect in the Mouse out, as in the tremor cage or light box motility test can be proven. In these tests, an oral or subcutaneous dose of 2.5 mg / kg / day registered the spontaneous motor activity of the test animals. In an oral dose of approximately 10 mg / kg / day, the new compounds antagonize the stimulatory effects of the in rats for more than four hours Amphetamine, as used in an electroshock avoidance test in which the animals are pressed by pressing a button to avoid an electric shock can be demonstrated. The new substances decrease in an analogous manner at an oral dose between approximately 0.1 and 10 mg / kg / day, the lever actuation of squirrel monkeys (squirrel monkeys), which have to perform this activity in order to avoid an electric shock. In this test increases the number of electric shocks suffered in parallel with the dose used (Sidmann method). One intravenous Administration of the new compounds to rabbits at a dose of approximately 2 mg / kg / day causes a cataleptic-like appearance State from which the animals can easily be woken up (unchanged righting reflex). In

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an intravenous dose of approximately 10 mg / kg / day the products of the process do not breathe in anesthetized cats, however they exert a depressive effect on the plexor and patellar reflexes of these experimental animals the end. The new compounds can therefore be used as neuroleptic agents, e.g. in the treatment of restlessness, aggressiveness or anxiety in warm-blooded animals, preferably Mammals, or as analgesics. The process products can also be used as intermediates be used for the production of other valuable, especially pharmacologically active compounds.

Preferred compounds with regard to their neuroleptic and analgesic effects are those of the formula I, wherein Ph substitutes unsubstituted 1,2-phenylene or 1,2-phenylene by a maximum of 2 substituents selected from the group consisting of lower alkyl, hydroxy, mercapto, lower alkoxy, Lower alkylenedioxy, lower alkylthio, halogen, lower (hydroxy, alkoxy, mono-, di- or trihalo) -alkyl, nitro, Amino, di-lower alkylamino, lower alkanoyl, lower alkylsulfinyl or lower alkylsulfonyl, each of the symbols R- ,, Rp

and R ^ is hydrogen or lower alkyl, any of the .Rests alk, and alkp lower alkylene, which is the nitrogen atom from the spiro carbon atom through two ring carbon atoms

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separates, means, R ₁ , for hydrogen, lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, cycloalkenyl-lower alkyl or H-Ph-C H _p -, where η 0 to. 4 denotes, Rp. Denotes two hydrogen atoms, hydrogen and lower alkyl or oxo, and R, - denotes hydrogen, lower alkyl or hydroxy-lower alkyl, a lower alkanoyl, H-Ph-lower alkanoyl or H-Ph-carbonyl derivative of these Compounds in which R ₁ . and / or R ^ is hydrogen or Ph or Rg contains hydroxy, mercapto or amino, N-oxides or lower alkyl quaternary derivatives of these compounds in which Ru and R ^ are different from hydrogen and Ph is different from (amino) -1,2 -phenylene is different, and their salts, in particular therapeutically useful acid addition salts.

The compounds of formula I are valuable in terms of their neuroleptic and analgesic effects, wherein Ph 1,2-phenylene, (lower alkyl) -1,2-phenylene, (hydroxy) -1,2-phenylene, Mono- or di- (lower alkoxy) -1,2-phenylene, (lower alkylenedioxy) -1,2-phenylene, (lower alkylthio) -1,2-phenylene, (Halogen) -1,2-phenylene, (lower α-hydroxyalkyl) -1,2-phenylene, (Trifluoromethyl) -1,2-phenylene, (nitro) -1,2-phenylene, (Amino) -1,2-phenylene, (di-lower alkylamino) -1,2-phenylene, Means (lower alkanoyl) -1,2-phenylene, (lower alkylsulphinyl) 1,2-phenylene or (lower alkylsulphonyl) -1,2-phenylene,

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each of the radicals R ₁ , R ₂ and R- is hydrogen or lower alkyl, each of the radicals alk- and alkp is lower alkylene, which separates the nitrogen atom from the spiro carbon atom by 2 ring carbon atoms, R ₁ , for hydrogen, lower alkyl , Cycloalkyl or cycloalkyl-lower alkyl containing 3 to 7 ring members or H-Ph-C Hp -, in which η is 0 to 4, R, - is two hydrogen atoms, hydrogen and lower alkyl or oxo, and Rg is hydrogen, lower alkyl or hydroxy -lower alkyl denotes lower alkanoyl derivatives of these compounds in which R ^ and / or R ^ denotes hydrogen or Ph or Rg contains hydroxy, mercapto or amino, N-oxides or lower alkyl quaternary ammonium derivatives of these compounds in which Rh and R ^ are different from hydrogen and Ph is different from (amino) -l, 2-phenylene, or their therapeutically useful acid addition salts. Compounds of the general formula II are preferred

(II),

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- ίο -

wherein R "is hydrogen, lower alkyl, hydroxy, lower alkoxy, halogen, lower α-hydroxy-alkyl, trifluoromethyl or lower alkanoyl, each of the radicals Rg, R _Q and R _{11 is} hydrogen or _{lower alkyl, R 10 is} lower alkyl, 3 to 7 ring members containing cycloalkyl or R _{7 is} -PtLenyl, and R, is hydrogen, lower alkyl, hydroxy-lower alkyl or lower alkanoyl, or lower alkyl -quaternary ammonium derivatives of compounds in which R _{12 is} lower alkyl or hydroxy-lower alkyl, and their therapeutically useful acid addition salts .

Compounds of the formula II in which R _{17 is} hydrogen, alkyl, hydroxy, alkoxy, halogen, α-hydroxyalkyl, trifluoromethyl or alkanoyl, and each of the radicals Rg, R _Q and R _{11 is} hydrogen or methyl, R _{10 are particularly valuable} Is methyl, cyclohexyl or R “-phenyl, R _1? represents hydrogen, methyl, hydroxymethyl or acetyl, where alkyl, alkoxy or alkartoyl contain at most 4 carbon atoms, or their therapeutically useful acid addition salts, and also compounds of the formula II in which R ₇ denotes hydrogen, lower alkyl, hydroxy, lower alkoxy, halogen or trifluoromethyl, each of the radicals Rg, R _q and R ,, represents hydrogen or methyl,

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R ₁ denotes methyl, cyclohexyl or R “-phenyl, and R-. _{p stands} for hydrogen, methyl, hydroxymethyl or acetyl, and their therapeutically useful acid addition salts.

Particularly noteworthy are the compounds of the formula II in which R ₇ denotes hydrogen, methyl, methoxy, B "luor, chlorine, 1-hydroxyethyl, trifluoromethyl or acetyl, and each of the radicals Ro, R _Q , R ₁₁ and R ₁ " denotes hydrogen or Is methyl, and R ₁₀ is R "-phenyl, and of these in particular 1-phenyl-4-oxo-8- [5-methoxy- or 5- (1-hydroxyethyl) -2,3-dihydro-2-benzofury ! methyl 3-1,3,8-triazaspiro (4,5) decane, or their therapeutically useful acid addition salts, primarily the levorotatory form of these compounds, which have excellent effects in the test systems described above, especially in the Sidman test exhibit.

The new compounds are produced according to methods known per se, e.g. by being

a) Compounds of the general formulas III

and IV

^r t R- O

Ph X "^ X (III) and Y ^ 0 ' (iv) ·,

N - C = R _c 1 5

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wherein X is a reactive esterified hydroxy group or Amino means and Y means imino or two reactive ones. esterified hydroxyl groups, only one of the radicals X and Y contains a nitrogen atom, or a metal salt of these amines or imines, condensed or

b) Compounds of the general formulas V and VI

(V) and

Z = C = R ₅ . (VI),

where Z denotes oxo, hydrogen and amino or two reactive, functionally modified hydroxy or amino groups, only one of the radicals Z and R ^ containing an oxo group, condensed or

c) a dehydro and / or hydroxy derivative of a compound of the general formula VII

0 alk _n CNR,

Iv

Ph · C * N

2. * 0 "^ R ₀ ^N alk ^ / ^X N - C = R,

(VII),

where W is a free or reactive functionally ab

converted group of the formula HO -C-R., means or

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represents the group of the formula -CH-R, if

a double bond starts from at least one of the carbon atoms in the 2-position, reduced, and, if desired, converts a compound obtained into another compound according to the invention, or converts a compound obtained into its salts, acyl derivatives, N-oxides or quaternary ammonium compounds, and / or, if desired, converting a salt obtained into the free compound and / or, if desired, separating a mixture of isomers or racemates obtained into the individual isomers or racemates, and / or, if desired, resolving racemates obtained into the optical antipodes . A reactive, functionally modified hydroxyl group in the above-mentioned starting materials is preferably one with a strong mineral acid or sulfonic acid, e.g. sulfuric acid, methane, ethane, benzene, p-toluene or camphorsulfonic acid, in particular with a hydrohalic acid, e.g. hydrochloric or hydrobromic acid esterified hydroxy group. The substituent Z can also represent hydroxyl groups etherified with lower alkanols or glycols, for example methanol, ethanol or ethylene glycol. If the substituent Z is reactive, functionally modified amino groups, for example if R ₁ - is oxo

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Z can represent, for example, two imidazolyl groups. Are metal salts of the above amines or imines preferably alkali metal, e.g. lithium, sodium or potassium salts.

The above reactions are carried out according to methods known per se, in the presence or absence of Diluents, preferably those which are inert to the reagents and which dissolve them, Catalysts, condensation or reducing agents and / or in an inert atmosphere, with cooling, at room temperature or carried out at elevated temperatures, at normal or elevated pressure. Be condensing agents preferred in the reactions mentioned under a) and b). When using reactive esters or acid derivatives are the condensing agents are basic reagents, e.g. alkali metal or alkaline earth metal carbonates, hydroxides or -lower alkanolates, such as sodium, potassium or calcium carbonate, sodium or potassium hydroxide, methylate or ethylate, but also organic nitrogen bases, e.g. aliphatic or aromatic tertiary amines, such as tri-lower alkylamines, e.g. triethylamine; Pyridine or collidine. If acetals are used in the condensation shown under b), preferably acidic agents, e.g. the above-mentioned strong mineral

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or sulfonic acids are used. According to the reaction b) condensation carried out in which the compound of the formula Z = C = R, - is formamide preferred. This reagent is to be used in at least 2 molar equivalents in order to prepare the compounds of the formula I, To get ammonia and carbon dioxide.

The reduction according to process variant c) is preferably carried out with catalytically activated or nasal Hydrogen, e.g. hydrogen, in the presence of a platinum, palladium or nickel catalyst, or with Hydrogen, which is produced by the action of alcohols or weak acids on metals, e.g. lower alkanols on light metals such as alkali metals or their amalgams, or lower alkanecarboxylic acids on heavy metals such as zinc, Cadmium or iron, receives, carried out. It can also reduce agents, preferably complex light metal hydrides, e.g., alkali metal aluminum hydrides or alkali metal borohydrides such as lithium aluminum hydride or sodium borohydride, optionally in the presence of a Lewis acid such as aluminum chloride.

Compounds obtained can be converted into other compounds according to the invention by methods known per se will. For example, a obtained primary or secondary amine can be mixed with reactive esters of corresponding

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the alcohols, for example lower alkanols, are implemented. Primary or secondary amines obtained can also be acylated. A reactive functional derivative of a corresponding acid, for example acid halides or anhydrides, is used for this purpose. On the other hand, acyl derivatives obtained, for example esters or amides, for example hydrolyzed with acidic or basic hydrolyzing agents, and ketones f or amides to the corresponding a-hydroxyalkyl-1,2-phenylene compounds or lower alkylamino or -imiho compounds, for example with complex light metal hydrides such as sodium borohydride or lithium aluminum hydride, are reduced. Finally, tertiary amines obtained can be converted into the N-oxides, preferably by treatment with hydrogen peroxide or percarboxylic acids, for example peracetic or perbenzoic acid, or, for example, with lower alkyl halides or sulfonates, for example chlorides, bromides, iodides or p-toluenesulfonates quaternary compounds are converted.

Depending on the process conditions, the end product is obtained in free form or in the Γη of the invention included form of its acid addition salts. Received. Salts can in a manner known per se, for example with alkalis or ion exchangers, are converted into the free compound. On the other hand, the free base obtained can with organic or inorganic acids form salts. For the production of acid addition salts, in particular acid

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Ren, which give therapeutically useful salts, used. Such acids are e.g. inorganic acids, such as strong mineral acids, e.g. hydrohalic acids such as hydrochloric or hydrobromic acid, Sulfuric acid, phosphoric acid or perchloric acid Jordanian Acids, e.g. carboxylic acids or sulfonic acids, such as formic, acetic, propionic, amber, glycol, lactic, apple,. Wine, lemon, ascorbic, maleic, ilydroxymalcine odor Pyruvic acid; Phony.! Vinegar-, Bonzoe-, p-Amlno-bon / .oo-, Anthranil, p ~ IIydroxy-bonzoe, salicylic or p-amino-salicylic acid, Kmbonsäurc, nicotinic acid, Mcthansulfon-, Aothanßulfon-, Ilydroxyäthansulfon-, Aethylciujulfonsäurc; I halogenobenzene sulfone, Toluenesulphonic, naphthalenesulphonic acids or sulphanilic acid or cyclohexylsulphamic acid; Methionine,

* ι ι

Tryptophan, lysine, or arginine.

, These or other salts of the new compound, such as the picrates, can also be used to purify the obtained Free compounds serve by converting the free compound into salts, separating them and turning them out of the salts clears the free connection.

As a result of the close relationship between the new compound in free form and in the form of its acid addition salts are above and below under the

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free connection in a meaningful and appropriate manner, if applicable also to understand the corresponding acid addition salts.

The invention also relates to those embodiments of the method, after which one of a Compound obtainable as an intermediate at any stage of the process runs out and the missing Performs process steps, or in which the starting materials are formed under the reaction conditions or in which the reaction components are used in the form of a salt. For example, the amines mentioned above can be used in Form of their alkali metal salts can be used.

In the process of the present invention, those starting materials are preferably used, which lead to the compounds described at the beginning as being particularly valuable.

The starting materials are known or, if new, according to methods known per se, such as in the Examples illustrated or described in the literature cited. The 1- (2,3-dihydro-2-benzofuryl) alkanol derivatives or the corresponding alkylamines, and also the 1,3,8-triazaspiro (4,5) are decane in U.S. Patents 3,459,860; 3,470,185 and 3,238,216 described. The 5-bis (2-hydroxyalkyl) -2,3-dihydro-4-

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imidazolones of the formula IV are analogous to the latter Connections made. However, instead of 4-piperidone, corresponding open-

chain, free or esterified dihydroxy alkanes, e.g. 1,5-dihydroxy-3-pentanone. The latter connection is reacted according to Strecker with ammonia or a corresponding amine and hydrogen cyanide, the obtained α-amino nitrile hydrolyzed to the corresponding amide and the latter ring-closed analogously to reaction b). The hexahydroisonicotinamide starting materials the process variant b) are analogous, from 1-benzyl-4-piperidones according to the Strecker synthesis, cleavage of the benzyl group of the amide obtained by hydrogenation and conversion of the amide obtained 1-unsubstituted amide prepared according to reaction a). A similar condensation is used for the manufacture of starting materials of process variant c) used. A double bond is preferably present in the reaction components introduced and then the compounds of the formulas III and IV shown in reaction a) corresponding Dehydro derivatives condensed. The dehydro-spiro compounds used for reaction c) can preferably by a ring-closing condensation analogous to reaction b) can be produced. However, instead of lower alkane derivatives, reactive Nlederalkansäurederivate, e.g. lower alkyl-ortho-

2 0 9 8 31/1151 BATH ORIGINAL

ester or imino ester. Finally, connections can of "Formula VII, in which W stands for the group of the formula"

HO-C-R-; stands, by addition of 2-benzofuran-car-

I ³

boxaldehydes or alkanones, or their 2,3-dihydro derivatives to 8-unsubstituted 1,3 * 8-triazaspiro (4,5) Decans are made.

Starting materials and end products, which are mixtures of isomers, can be prepared according to methods known per se

into the individual isomers, e.g. by fractional distillation, crystallization and / or chromatography be separated. Racemic products can be used in the optical antipodes, e.g. when their diastereoisomers are separated Salts, e.g. through fractional crystallization. the d- or 6-tartrates, -maleates, -andelates, -N-acetylphenyl-alaninate or -Camphorsulfonate and conversion of the dxastereoisomeric salts or esters into the free "anti pods, be separated. The mentioned ester intermediates can also be used directly in reaction a).

The phar.Tiakologiseh usable compounds of The present invention can be used, for example, for the manufacture of pharmaceutical Preparations have been used which are effective Amount of Aktivsubstar.JS together or in a mixture with inorganic ones or organic, solid or liquid, pharmaceutically acceptable carriers, which are

20983 1/11 5 T
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toral or parenteral administration. Preferably one uses tablets or gelatin capsules, which contain the active ingredient together with diluents, e.g. lactose, dextrose, Sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, "e.g. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binding agents, e.g. magnesium aluminum silicate, starches such as corn, Wheat, rice or arrowroot starch, gelatine, tragacanth, • methyl celulose, sodium carboxymethyl cellulose and / or Polyvinylpyrrolidone, and, if desired, spreading agents, e.g. Starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or mixtures, or adsorbents, Colorings, flavorings and sweeteners. Injectable c Preparations are preferably isotonic aqueous solutions or suspensions, suppositories primarily fat emulsions or suspensions. Pharmaceutical preparations

·.
can be sterilized and / or contain auxiliaries, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts to regulate the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, may further contain pharmacologically meaningful substances, have been described in

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methods known per se, for example by means of conventional mixing, granulating or coating processes. and _f contain from about 0.1 # to about 75 #, in particular from about 1 # to about 50 ^ of the active ingredient.

For veterinary medical use, parenteral, for example intravenous or intramuscular, use are in particular usable solutions or. Suitable for suspensions. These can be in a preferred dose range of approximately 0.3 to 2.5 mg / kg / day.

The following examples serve to illustrate the invention. Temperatures are given in degrees Celsius.

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2098 3 _1iv1:; 1J1 ν

Example 1 :

A mixture of 3 * 7 g of 2-bromomethyl-5-methoxy-2., 3-dihydro-benzofuran, 3 * 6 g of 1-phenyl-4-oxo-l, 3 * 8-triazaspiro (4,5) decane, 6 g of anhydrous sodium carbonate and 50 ml of 2-propanol are refluxed for three days. The reaction mixture is then filtered and the filtrate is evaporated under reduced pressure. The residue crystallizes
after vigorous shaking in a mixture of 50 ml of diethyl ether and 50 ml of water. The product is recrystallized twice from ethanol. The l-phenyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -l, 3 * 8-triazaspiro (4,5) decane of the formula is obtained

which melts at 191-192 °.

The product is dissolved in acetone and 6 normal hydrochloric acid is added. The crystalline hydrochloride is obtained which at 29O (with decomposition)
melts.

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Example 2:

In a manner analogous to Example 1, a mixture of 2.8 g of 2-bromomethyl-2,3-dihydro-benzofurane, 3 g of 1-phenyl-4-oxo-1,318-triazaspiro (4,5) decane, 6 g of anhydrous sodium carbonate and 40 ml of 2-propanol for 3 days under reflux cooked and worked up. After recrystallization from acetone-ethanol, 1-phenyl-4-oxo-8- (2,3-dihydro-2-benzofuryymethyl) -1,3,8-triazaspiro (4,5) decane is obtained, which melts at 202-205 °.

Example 3 ^:

A mixture of 2.7 g of 2-bromomethyl-5-fluoro-2,3-dihydrobenzofuran, 2.7 g of l-phenyl-4-oxo-l, 3,8-triazaspiro (4.5) decane, 5 g of anhydrous sodium carbonate and 45 ml 2-Propanol is treated in the same way as in Example 1. The l-phenyl-4-oxo-8- (5-fluoro-2,3-dihydro-2-benzofurylmethyl) -l, 3i8-triazaspiro (4,5) decane is obtained, which after recrystallization from ethanol melts at 188-191.

The 2-bromomethyl-5-fluoro-2,3-dihydro-benzofuran used as the starting material is made as follows:

A mixture of 125 g of 4-fluorophenyl, 3OO ^m l acetone, 160 g potassium carbonate and 135 g of allyl bromide is boiled for 8 hours under reflux and allowed to stand overnight. The reaction mixture is then diluted with 600 ml of water and the

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Layers separated. The aqueous layer is extracted twice with 450 ml of methylene chloride each time. The United organic extracts are mixed with 225 ml of one of the above washed aqueous sodium hydroxide solution, dried, filtered and the Piltrat evaporated. You get that l-allyloxy-4-fluoro-benzene.

60 g of 1-allyloxy-4-fluoro-benzene are heated to 220 (internal temperature) for 2.5 hours. After cooling down the 2-allyl-4-fluorophenol is obtained.

A mixture of 60 g of 2-allyl-4-fluorophenol and 102 g of acetic anhydride are refluxed for 3 hours. The acetic acid formed is reduced under reduced The pressure is separated off and the residue is distilled. One obtains the l-acetoxy-2-allyl-4-fluoro-benzo]., Which at 118-121 / 14 mm / Hg boils.

A solution of 42 g of bromine in 120 ml of carbon tetrachloride is added dropwise to a solution of 51 S 1-Acetoxy-2-allyl-4-fluoro-benzene in 150 ml carbon tetrachloride given. After the addition has ended, the reaction mixture is stirred for 1.5 hours and then saturated with 60 ml treated aqueous sodium carbonate solution and 100 ml of water. The organic layer is separated, dried, filtered and evaporated under reduced pressure. 1,2-Dibromo-3- (2-acetoxy-5-fluorophenyl) propane is obtained.

BAO ORIGINAL

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A solution Ύοη 15 g of sodium methylate in 250 ml Ethanol is added dropwise to a solution of 90 g of 1,2-dibromo-3- (2-acetoxy-5-fluorophenyl) propane given in 125 ml of ethanol. The reaction mixture is under for 2 hours Boiled reflux, filtered and the 'Piltrat evaporated under reduced pressure. The residue is washed with water diluted and extracted with methylene chloride. The methyl chloride extract is dried, filtered and the Piltrat evaporated. The residue is distilled. You get 2-bromomethyl-5-fluoro-2,3-dihydro-benzofuran, which boils at 135-139 ° / 15 mm / Hg.

Example 4.

A mixture of 1.1 g of 2-bromomethyl-5-methoxy-1,2-dihydro-benzofuran, 1.1 g of 1-cyclohexyl-4-oxo-l, 3,8-triazaspiro (4,5) decane, 3 S sodium carbonate and 25 ml 2-propanol is refluxed for 3 days. The reaction mixture is then filtered off and the piltrate under reduced pressure Evaporated pressure. The residue is treated with a mixture of 50 ml of diethyl ether and 50 ml of water. The ether layer is separated off and extracted with aqueous citric acid. The combined acid extracts are with ammonium hydroxide made basic and extracted with diethyl ether.

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The ether extracts are dried and evaporated. The residue is recrystallized from ethanol. 1-Cyclohexyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benz ο-furyl-methyl) -l, 3. »8-triazaspirq (4,5) decane is obtained, which melts at I55-156 ^0.

Example 5 ^:

A solution of 50 gd, β-1-phenyl-4-0X0-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -1,3,8-triazaspiro (4,5) decane (obtained according to Example 1) in 180 ml of acetone is admixed with a solution of 26.4 g of N-acetyl-6-phenylalanine in 350 ml of acetone with stirring and the mixture is concentrated to approximately 150 ml. The reaction mixture is left to stand in the refrigerator overnight and the resulting precipitate is filtered off. The salt A is obtained, which ^{melts at IO3-105 0} (with decomposition). The mother liquor is further concentrated to about 800 ml and the precipitate obtained in the cold is filtered off. The salt B is obtained, which melts at 90-105 °.

J> 1 g of the salt A is crystallized from 325 ml of ethanol which contains 6 ml of water. Then, 26 g of recrystallized material from the zurückgevionnenen 325 ^m l of ethanol containing 4 ml of water. Finally one lets

2 0 9 8 31/1151

Recrystallize 24.5 g of the recovered material from 450 ml of ethanol. The purified salt is taken up in water, the mixture is made basic with aqueous ammonia and extracted with chloroform. The extract is dried and evaporated. BI- phenyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -l, 3,8-triazaspiro (4,5) decane, which ^{melts at 185-188 0} , is obtained , [α] = -12.4 ° (chloroform).

The salt B is taken up in water, the mixture made basic with aqueous ammonia and with chloroform extracted. The extract is dried and evaporated. 18.1 g of the residue are taken up in 450 ml of acetone and the Solution is with a solution of 9 * 55 g of N-acetyl-d-phenylalanine taken up in 180 ml of acetone. The mixture is concentrated to about 500 ml and 21 g of that obtained in the cold Precipitates are first recrystallized from 400 ml of ethanol which contains 2 ml of water. One lets then 17 g of the recovered material from 3OO ml of ethanol Recrystallize. The salt obtained is converted to the free base as shown above. The d-1-phenyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -1,3,8-triazaspiro (4,5) decane is obtained, which melts at 184-186, [α] "= + 12.4 ° (chloroform).

209831/1151

Example 6:

A solution of either &, £ - or B -1-phenyl-4-. oxo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -l, 3,8-triazaspiro (4.5) decane in 100 ml of acetone and 30 ml of ethanol is first mixed with 0.8 ml Methanesulfonic acid and then treated with 20 ml of water and 200 ml of diethyl ether. The precipitate obtained is filtered off and recrystallized from water. Either the d, ß - or the i l-phenyl-4-oxo-8- (5-methoxy-2 _i 3- ^| aihydro-2-benzofurylmethyl) -1.3 are obtained. » 8-triazaspiro (4,5) decane methanesulfonate hemihydrate. Both salts melt at 188-190 ⁰ .

Example 7:

■ A mixture of 6.6 g of 2-bromomethyl-7-methoxy-2,3-dihydro-benzofuran, 6.3 S 1-phenyl-4-oxo-1,3 * 8-triazaspiro- (4,5) decane , 12 g of sodium carbonate and 100 ml of 2-propanol are refluxed for 3 days. After cooling, the reaction mixture is filtered off, the piltrate is evaporated under reduced pressure and the residue is taken up in diethyl ether. The solution is shaken with 5% hydrochloric acid, the suspension obtained is filtered, the precipitate is suspended in water and the mixture is washed with aqueous ammonia

209831/1 151

made basic. The reaction mixture is extracted with chloroform, the extract is dried, filtered and evaporated. The residue is recrystallized from ethanol. The 1-phenyl-4-oxo-8- (7-methoxy-2,3-dihydro 2-benzofurylmethyl) -1,3,8-triazaspiro (4,5) decane is obtained, which melts at I70.

. Example 8:

A mixture of 12.5 g of 2-bromomethyl-4- and 6-methoxy-2,3-dihydro-benzofuran (2: 1), 12 g 1-phenyl-4-oxo-1,3 * 8-triazaspiro (4,5) decane, 25 g of sodium carbonate and 200 ml of 2-propanol are refluxed with stirring for 3 days. After cooling, the reaction mixture is filtered, the piltrate evaporated and the residue taken up in diethyl ether. The solution is shaken with 5% hydrochloric acid, which aqueous solution made basic with ammonia and extracted with diethyl ether. The extract is dried, evaporated and the residue is chromatographed on silica gel. The column is eluted with benzoil-methanol (9: 1). First an eluate is obtained which is the l-phenyl-4-oxo-8- (4-methoxy-2,3-dihydro-2-benzofurylmethyl) -1,3,8-triazaspiro (4,5) decane, contains. In the IR spectrum, this shows bands at 3193, 1695, 1590, 1195, 804, 749 and 690 cm ~. According to this product, the 1-phenyl-4-oxo-8-

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(6-methoxy-2,3-dihydro-2-benzofurylmethyl) -1,3i8-triazaspiro (4,5) decan eluted. This product has a similar IR spectrum in which the band at 804 cm is absent, while a new band appears at 785 cm. The two Isomers show a thin layer or an omatogram on silica gel, with the solvent mixture R mentioned above, values of 6.0 or 7 * 0.

The starting material is prepared as follows: A mixture of 100 g of 3-methoxyphenol, 70 ml Allyl bromide, 120 g potassium carbonate and 200 ml acetone - is refluxed with stirring for 8 hours. The reaction mixture is then diluted with water and made up with 5OO ml Diethyl ether extracted. The extract comes with a $ 5 aqueous sodium hydroxide solution and washed with water, dried and evaporated. 3-Allyloxy-anisole is obtained. This is taken up in 200 ml of N, N-dimethyl aniline and the mixture refluxed for 2 hours. After cooling, the reaction mixture is poured onto crushed ice and acidified with hydrochloric acid. The mixture is extracted with diethyl ether and the extract is washed with water and shaken with a 5 $ aqueous sodium hydroxide solution. The aqueous phase is acidified with hydrochloric acid and extracted with diethyl ether. The extract will dried, evaporated and the residue refluxed with 125 ml of acetic anhydride for 3 hours. The Rea-

209831/1151

tion mixture is evaporated under reduced pressure, the residue is distilled and at 156 - collected I58 ^0/15 mm Hg .erhaltene fraction. The 2: 1 mixture of 3-acetoxy-4-allyl-anisole and 3-acetoxy-2-allyl-anisole is obtained.

A solution of 53 g of the 2: 1 mixture of 3-acetoxy-4-allyl-anisole and 3-acetoxy-2-allyl-anisole in 150 ml of carbon tetrachloride is added dropwise, inside

ο

^ψ half an hour, with stirring and cooling below 25 , mixed with 4l g of bromine in 50 ml of carbon tetrachloride. The mixture is washed with an aqueous sodium hydrocarbonate solution, dried and evaporated. The residue is taken up in 75 ml of ethanol and a solution of 14.5 g of sodium methylate in 50 ml of ethanol is added to the solution, while stirring, over the course of half an hour. The reaction mixture is refluxed for 1 hour, cooled and filtered and the piltrate is evaporated under reduced pressure. The concentrate is diluted with water, extracted with chloroform, the extract is dried and evaporated. The 2: 1 mixture of 2-bromomethyl-4-methoxy-2,3-dihydro-benzofuran and 2-bromomethyl-6-methoxy is obtained -2,3-dihydro-benzofurans, which is used without further purification.

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Example 9 ^:

A mixture of 3.1 g of 2-bromomethyl-2-methyl-5-methoxy-2,3-dihydro-benzene of uran, 2.9 g of l-phenyl- ⁱ f-oxo-l, 3,8-triazaspiro ( 4.5) decane, 6 g of sodium carbonate and 50 ml of 4-methyl-2-pentanone are refluxed with stirring for 1 week. The reaction mixture is cooled, filtered and the piltrate washed with water and 5% hydrochloric acid. The combined aqueous solutions are basified with ammonia and extracted with chloroform. The extract is dried and evaporated under reduced pressure and the residue is chromatographed on silica gel. The column is eluted with a mixture of chloroform-diethylamine (9: 1), the l-phenyl-4-oxo-8- (5-methoxy-2-methyl-2,3-dihydro-2-benzofurylmethyl) - l, 3,8-triazaspiro (4.5) decane, which in thin-layer chromatography with the same stationary and mobile phase gives an R value of 6.0. Its hydrochloride melts at 280 - 282 (with decomposition).

The starting material is prepared as follows: A mixture of 100 g of 4-methoxyphenol, 73 g of 3-chloro-2-methyl-propene, 117 S potassium carbonate and 200 ml of acetone is refluxed with stirring for 12 hours. After cooling, the reaction mixture is diluted with water and extracted with diethyl ether. The extract comes with a

509831/1 1B1

aqueous sodium hydroxide solution washed, dried and evaporated under reduced pressure. The 4-methallyloxyanisole is obtained.

This product is diluted with the same volume of Ν, Ν-dimethylaniline and the mixture for 6 hours Boiled under reflux. After cooling, the mixture is poured onto ice and acidified with hydrochloric acid. The mixture is extracted with diethyl ether, the extract is washed with water, dried and evaporated under reduced pressure. The residue is taken up in petroleum ether and the mixture with a solution consisting of 35 g of potassium hydroxide, 25 ml of water and 100 ml of methanol is extracted. the aqueous phase is diluted with water, acidified with hydrochloric acid, extracted with diethyl ether, the extract dried and evaporated. The 2-MethaiIyI-4-methoxyphenol is obtained.

66 g of 2-methyl-4-methoxyphenol are added

a solution of 122 g of mercuric chloride in 300 ml of water and the mixture is stirred overnight at room temperature. The reaction mixture is then filtered and recrystallized from ethanol. 5-Methoxy-2-methyl-2,3-dihydro-2-benzofurylmethyl mercuric chloride is obtained, which melts ^{at 1} JO. 44.5 g of this product are suspended in 150 ml of carbon tetrachloride and the suspension is added dropwise, with stirring at 0-5 °, with a solution of 5 * 75 ml of bromine in ^ O ml of tetra-

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Chlorocarbon. After 6 hours the mixture is filtered and evaporated the Piltrat. The 2-bromomethyl-2-methyl ^ -methoxy ^, 3-dihydro-benzofuran is obtained.

Example 10:

A mixture of 1 g of 1-phenyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benzofuryl-methyl) -1,3,8-triazaspiro (4,5) dec-2-en , 0.1 g of 1Obigem palladium on carbon catalyst and 50 ml Glacial acetic acid becomes at room temperature and under a pressure of 2.7 atmospheres until the theoretical amount has been absorbed Hydrogenated hydrogen. The mixture is then filtered, the filtrate concentrated under reduced pressure, the concentrate diluted with water and made basic with ammonia. The precipitate obtained is filtered off and recrystallized from ethanol. 1-Phenyl-4-oxo-8- (5-methoxy-2,3-dihydro) is obtained -2-benzofurylmethyl) -1,3,8-triazaspiro (4,5) decan, which melts at 191-192. The product is the same as that of the example 1 identical.

The same product can also be obtained by analogous reduction of l-phenyl-4-oxo-8- (5-methoxy-2-benzofurylmethyl) -. 1,3,8-triazaspiro (4,5) decans obtained.

The starting material is prepared as follows: a) A mixture of 6 g of 1-benzyl-4-phenylaminohexahydro-isonicotinamide, 2 g of 10% palladium on carbon

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Catalyst, 90 ^m l of glacial acetic acid and 10 ml of water is hydrogenated at 2.7 atmospheres and 60 until the theoretical amount of hydrogen. The mixture is filtered, the piltrate is evaporated under reduced pressure and the residue is taken up in water. The mixture is made basic with ammonia, extracted with chloroform, the extract is dried and evaporated. The residue is recrystallized from ethanol. The 4-phenylamino-hexahydroisonicotinamide is obtained, which melts at 209-210 °.

A mixture of 1.9 S 4-phenylamino-hexahydroisonicotinamide, 2.1 g of 2-bromomethyl-5-methoxy-2,3-dihydrobenzofuran, 4 g of sodium carbonate and 200 ml of .2-propanol are refluxed for 4 days, cooled, filtered and the piltrate evaporated under reduced pressure. The residue is in a mixture of 50 ml of diethyl ether and 50 ml Water absorbed and left to stand. The precipitate obtained is filtered off and recrystallized from ethanol. The 1- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -4-phenylamino-hexahydro-isonicotinamide is obtained, which melts at I50. A mixture of 2 g of 1- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -4-phenylamino-hexahydro-isonicotinamide. . 100 ml of trimethyl orthoformate and 25 mg of ρ-toluenesulphonic acid is carried out in a Soxhlet apparatus for 24 hours

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Boiled under reflux, passing the condensate through a molecular sieve., which eliminates the methanol, lets through. The reaction mixture is evaporated and the residue with a little methanol triturated. 1-Phenyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -1,3,8-triazaspiro (4,5) dec-2-ene is obtained.

b) A solution of 17 * 7 S 6-methoxycoumarin in 60 ml of chloroform is added dropwise with stirring at room temperature with 5 * 5 ml of bromine in 10 ml of chloroform. The reaction mixture is stirred overnight, 20 ml of a 20% aqueous sodium sulfite solution are added dropwise, the organic phase is separated off and the aqueous layer is washed with chloroform. The combined organic phases are washed with water, dried, filtered and evaporated under reduced pressure. The ~ $ _t K dibromo-6-methoxy-3,4-dihydrocoumarin is obtained.

A solution of 27.3 S 3j ^ ~ dibromo-6-methoxy-3,4-dihydrocoumarin in 20 ml of ethanol is added in portions to a mixture of 50 g of potassium hydroxide and 75 ml of ethanol, with stirring

o *

ren given at about 15. The reaction mixture is refluxed for 2.5 hours, concentrated, the concentrate diluted with water and with 6 normal hydrochloric acid acidified. The resulting precipitate is filtered off, washed with water and first from aqueous ethanol and then recrystallized from ethanol. The 5-methoxy-2-

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benzofurancarboxylic acid, which melts ^{at 174-178 0.}

A solution of 3,7 5-methoxy-2-benzofurancarboxylic acid in 50 ml of tetrahydrofuran and 50 ml of diethyl ether is added to a suspension of 1.8 g of lithium aluminum hydride in 25 ml of diethyl ether with stirring at room temperature. The mixture is stirred overnight, then 1.8 ml of water, 3.6 ml of a 12% aqueous sodium hydroxide solution and 5.4 ml of water are added, the mixture is filtered and the piltrate is evaporated under reduced pressure. The residue taken up in diethyl ether, the solution washed with a saturated sodium hydrocarbonate solution and water, dried and evaporated. 2-Hydroxymethyl-5-methoxy-benzofuran is obtained, which shows bands at 325O, 160O, 1205, II60, 1010 and 805 cm " ¹ in the IR spectrum.

A solution of 1.5 g of 2-hydroxymethyl-5-methoxybenzofuran in 50 ml of diethyl ether, 0.28 ml of phosphorus tribromide is added within 5 minutes while stirring at -70. The mixture is allowed to warm to room temperature and is stirred for 3 hours. The reaction mixture is then poured onto ice, the organic phase with a saturated, aqueous sodium hydrocarbonate solution and water, dried and evaporated. 2-bromomethyl-5-methoxy-benzofuran is obtained.

A mixture of 3.8 g of 2-bromomethyl-5-methoxy-benzofuran, 3.6 g of 1-phenyl-4-oxo-1,3. »8-triazaspiro (4,5) decan,

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2 g of sodium carbonate and 210 ml of 4-methyl-2-pentanone is refluxed with stirring for 3 days. The reaction mixture is filtered after cooling and the filtrate with water / water washed and extracted with 5% hydrochloric acid. The precipitate obtained is filtered off and washed with water / water. The 1-phenyl -4-oxo-8- (5-methoxy-2-benzofurylmethyl) -1, 3,8-triazaspiro (4,5) is obtained Dekane hydrochloride, which melts at 26O-265. The product is taken up in water, the mixture is made basic with ammonia, extracted with diethyl ether and the extract evaporated. The corresponding free base is obtained.

Example 11:

A mixture of 6 g of 1- (5-methoxy-2,3-dihydro-2-benzofuryymethyl) -4-phenylamino-hexahydroisonicotinamide and 20 ml of formamide is heated to 170 for 12 hours, cooled and diluted with 10.0 ml of water. The reaction mixture is extracted twice with 50 ml of chloroform, the extract dried and evaporated under reduced pressure. The residue is recrystallized from ethanol. You get the l-phenyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -l, 3,8-triazaspiro (4,5) decane, which melts at I9O-I92. The product is the same as that of Example 1 identical.

209831/1151

Example 12:

A mixture of 15 * 5 g of 2-bromomethyl-5-methoxy-2,3-dihydro-benzofuran, 10 g of 4-0xo-l, 3 * 8-triazaspiro (4.5) decane, 20 g of sodium carbonate and 100 ml of isopropanol is refluxed with stirring for 3 days. The reaction mixture is then cooled, filtered and the piltrate evaporated under reduced pressure. The residue is taken up in methylene chloride and the solution is extracted with 5% methanesulfonic acid. The aqueous phase is made basic with ammonia and extracted with chloroform. The extract is dried and evaporated. The 4-0xo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -1,3 * 8-triazaspiro (4,5) decane, which in the IR spectrum has bands at 3158, 1700, 160 and 1204 cm " ¹ shows.

The starting material is prepared as follows: A mixture of 38 S 1-benzyl-4-piperidone, 15 * 5 g Ammonium acetate and 120 ml of acetic acid are stirred at 45 ° with a solution of 14.3 S potassium cyanide in 40 ml of water offset. The reaction mixture is kept at room temperature for 24 hours stirred, then poured onto 200 g of ice and 260 ml of a saturated aqueous ammonia solution. The mixture is extracted with chloroform, the extract is dried and evaporated. 4-Amino-1-benzyl-hexahydro-isonicotinonitrile is obtained.

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A mixture of 10 g of 4-amino-I-benzyl-hexahydro-

isonicotinonitrile and 100 ml of OO ^ iger sulfuric acid heated to 70 for 10 minutes with stirring. The reaction mixture is then cooled, basified with ammonia and extracted with chloroform. The extract is dried and evaporated. 4-Amino-1-benzyl-hexahydroisonicotinamide is obtained.

A mixture of 20 g of 4-amino-1-benzyl-hexahydroisonicotinamide and 60 ml of formamide is heated to 170 with stirring for 12 hours. After cooling, the reaction mixture is poured into 300 ml of water and the mixture is extracted with chloroform. The extract is dried and evaporated. The 8-benzyl-4-oxo-1,3 * 8-triazaspiro (4,5) decane is obtained.

Dissolve 20 g of 8-benzyl-4-oxo-l, 3 * 8-triazaspiro (4,5) decanted into 200 ml of 90 $ iS ^he is acetic acid 5 g of lO ^ weight palladium on carbon catalyst and hydrogenated to the solution at 55 until the theoretical amount of hydrogen has been absorbed. The reaction mixture is filtered, the piltrate is evaporated and the residue is taken up in J> 0 ml of water. The solution is made basic with ammonia, extracted with chloroform, the extract is dried and evaporated. You get the 4-0xo-

i5) dean.

2 098 31/1151

example

A solution of 0.668 g of ß-2- (tosyloxymethyl) -5-methoxy-2,3-dihydrobenzofuran in 5 ml of dimethylformamide is mixed with 0.475 g of l-phenyl-4-oxo-l, 3,8-triazaspiro (4.5) decane and 0.15 g of sodium carbonate are added and the mixture is stirred at 110 ° for 6 hours. The reaction mixture is cooled, diluted with water and filtered off after 2 hours. f The residue is dried and recrystallized from benzene. The f? -L-phenyl- ² J-oxo-8- (5-methoxy-2,3-dihydrο-2-benzofurylmethyl) -1,3 * 8-triazaspiro (4,5) decane is obtained, which at 188-190 ⁰ melts, [α] = -11.9 ° (chloroform). The product is identical to that of Example 5. The starting material is prepared as follows: A solution of 0.97 S d * £ -5-methoxy-2., 3-dihydro-2-benzofurancarboxylic acid in 50 nil diethyl ether is mixed with 0.7 g of ^ -amphetamine while stirring. The precipitate obtained is filtered off and washed with diethyl ether. The corresponding salt is obtained, which melts at 134-142. It is dissolved in 125 ml of hot acetone and the solution is left to stand for 2.5 hours at room temperature. The precipitate obtained is filtered off, washed with acetone and redissolved in 60 ml of hot acetone. The precipitate obtained after standing for three hours is filtered off. The corresponding d-salt is obtained, which melts at I53-I62.

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The mother liquors obtained are concentrated to 60 ml and the solution is kept for 3 hours at room temperature ditched. The precipitate obtained is filtered off and recrystallized from acetone. You get the corresponding £ salt, which is found in I50-I65 melts ..

The two salts obtained are each in a minimal amount of a 6 normal hydrochloric acid added and the resulting solution extracted with diethyl ether. The extract becomes more saturated with water and washed aqueous sodium chloride solution, dried and evaporated. You get:

a) the d-5-methoxy-2,3 ~ dihydro-2.-benzofurancarboxylic acid, [cx3_ ^ = +37 (chloroform)

b) the corresponding ß-antipodes, t · ² ^ = ~ 3δ (chloroform).

A solution of 0.68 g of d-5-methoxy-2,3-dihydro-2-benzofurancarboxylic acid 0.15 g of lithium aluminum hydride is added to 25 ml of tetrahydrofuran and the mixture is 1 hour refluxed. After cooling, the reaction mixture is diluted with 0.15 ml of water and 0.3 ml of a 12% aqueous solution Sodium hydroxide solution and 0.45 ml of water are added, and the mixture is filtered and the piltrate evaporated under reduced pressure. The residue is taken up in benzene, the solution is filtered and the filtrate evaporated under reduced pressure. You get

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the iJ-2-hydroxymethyl-5-methoxy-2,3-dihydro-benzofuran, [α] = -49 ° (chloroform).

In an analogous manner, the ε-acid becomes the corresponding one d-alcohol reduced. [ct] n = + 45 (chloroform).

A solution of 0.5 g of £ -2-hydroxymethyl-5-methoxy-2,3-dihydro-benzofuran 0.75 ml of p-toluenesulphonic acid chloride are added to 5 ml of pyridine and the mixture stirred overnight at room temperature. The reaction mixture is then mixed with 5 ml of water and stirred for 10 minutes. Then the mixture is further diluted with water and extracted with benzene. The extract is 5-normal Hydrochloric acid, water and saturated aqueous sodium chloride solution, dried and washed under reduced! Evaporated pressure. The residue is triturated with diethyl ether. The £ -2- (tosyloxymethyl) -5-methoxy-2,3-dihydro-benzofuran is obtained, which melts at 8O-8l °.

Example 14:

A mixture of 10 g of l-phenyl-5-bis- (2-tosyloxyethyl) -2,3-dihydro-4-imidazolone, 3.2 g of 2-aminomethyl-5-acetyl-2,3-dihydro-benzofuran, 20 g sodium carbonate and 50 ml isopropanol is refluxed with stirring for 3 days. The reaction mixture is filtered hot, the piltrate under mixed

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reduced! Evaporated pressure and the residue with a Mixture of 50 ml of water and 50 ml of diethyl ether was stirred. The precipitate obtained is filtered off and recrystallized from acetone. The 1-phenyl-4-oxo-8- (5-acetyl-2,3-dihydro-2-benzofurylmethyl) -1,3,8-triazaspiro (4,5) decane is obtained, which melts at l66-l68 °.

The starting material is prepared as follows: A solution of 20 g of 1,5-dihydroxy-3-pentanone and 15 * 8 aniline in 70 ml of acetic acid with stirring at 45. A solution of 11.1 g potassium cyanide in 30 ^m l of water added drop by drop. The reaction mixture is left to stand at room temperature for 1 day, poured onto 100 g of ice and extracted with chloroform. The extract is dried and evaporated. A-phenylaminoa- (2-hydroxyethyl) -7-hydroxybutyric acid nitrile is obtained.

A mixture of 20 g of a-phenylamino-oc- (2-hydroxyethyl) -7-hydroxy-butyric acid nitrile and 90 g of 80% sulfuric acid is heated to 70 for 10 minutes and placed on ice poured. The mixture is made basic with ammonia, extracted with chloroform, the extract is dried and evaporated. The corresponding amide is obtained.

A mixture of 30 g of this amide and 60 ml of formamide is stirred at 170 ° for 12 hours. After cooling, the reaction mixture is diluted with water, with chloroform

209831/1161

The extract is dried and evaporated. The residue is taken up in 100 ml of pyridine, the solution is cooled to 5 and at this temperature, while stirring, 3 ² S p-toluenesulfonic acid chloride is added. The mixture is stirred overnight at room temperature , then slowly treated with 300 ml of water and the mixture extracted with chloroform. The extract is washed with 5% hydrochloric acid and water, dried and evaporated under reduced pressure. The 1-phenyl-5-bis- (2-tosyloxy- ethyl) -2,3-dihydro-4-imidazolone.

Example 15:

A mixture of 13 * 2 g of 2-bromomethyl-5-methoxy-2,3-dihydro-benzofuran, 10 g of 3-methyl-2,4-dioxo-1,3. » 8-triazaspiro (4,5) decane, 20 g sodium carbonate and 200 ml isopropanol. is refluxed with stirring for 3 days. The reaction mixture is filtered hot, the piltrate is evaporated and the residue is taken up in methylene chloride. The solution is shaken with 5 ^ ^r strength methanesulfonic acid, the aqueous phase made alkaline with ammonia and extracted with chloroform. The extract is dried and evaporated. To yield the 3-methyl-2,4-dioxo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -l, 3J8-triazaspiro (4,5) decane, which with I83 - I87 melts ⁰ .

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The starting material is prepared as follows: A solution of 20 g of 8-benzyl-3-methyl-2,4-dioxo-l, 3,8-triazaspiro (4,5) dekan [Jl Pharmaeo, 25_, 68l (1970)] ig in 200 ml of 90 ^ ^he aqueous acetic acid is about 5 g of a lO ^ weight palladium on carbon catalyst at 55 t> is hydrogenated to the theoretical amount of hydrogen. The mixture is then filtered off, the piltrate concentrated, the concentrate diluted with water and made basic with ammonia. The mixture is extracted with chloroform, the extract is dried and evaporated. The 3-methyl-2,4-dioxo-1,3,8-triazaspiro (4,5) decane is obtained.

Example l6:

A mixture of 10 g of 5-methoxy-benzofuran-2-carboxaldehyde, 13 g of l-phenyl - ^ - oxo-l ^ S-triazaspiroC ² ! - ^) decane, 0.5 ml of acetic acid and 200 ml of ethanol is in a nitrogen atmosphere Boiled under reflux for 5 hours. After cooling, 3 S of a 10 ^ strength palladium on carbon catalyst is added to the reaction mixture and the mixture is hydrogenated at 55 ° and 3.3 atmospheres until the theoretical amount of hydrogen has been absorbed. The reaction mixture is then heated to reflux, filtered hot, the

209831/1151

The filtrate was slowly cooled and the resulting precipitate
filtered off. The l-phenyl-4-oxo-8- (5-methoxy- 2, 3-dihydro-2-benzofurylmethyl) -1,3,8-triazaspiro (4,5) is obtained
dean, which melts ^{at 19I 0.} The product is with
identical to that of Example 1.

The raw material is produced as follows:
A mixture of 10 g of 2-hydroxymethyl-5-methoxy-

| benzofuran, 10 g of active manganese dioxide and 100 ml of methylene chloride is stirred for 24 hours at room temperature. That
The mixture is filtered, the residue is washed with hot methylene chloride and the combined filtrates are evaporated. The 5-methoxy-benzofuran-2-carboxaldehyde is obtained.

Example 17:

Manufacture of 10,000 tablets containing 1 mg of the active substance:

Components:

l-phenyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benzofuryl-

methyl) -1,3,8-triazaspiro (4,5) decane 10 g

Milk sugar 828 g

Cornstarch. 50 g

Polyethylene glycol 600 50 g

Talc powder 50 g

Magnesium stearate "12 g

Purified water q.G.

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Procedure:

All powders are sieved with a sieve with a mesh size of 0.6 mm. The active ingredient is then mixed with lactose, talc, magnesium stearate and half the starch in a suitable mixer. The other half of the starch is suspended in 25 ml of water and the suspension is added to the boiling solution of polyethylene glycol in 100 ml of water. The paste obtained is added to the powders _and granulated, if necessary with the addition of a further amount of water. The granules are dried overnight at 35, driven through a sieve with a mesh size of 1.2 mm and pressed into tablets with a diameter of 4.8 mm and which have a break groove.

Example 18;

Production of 10,000 tablets containing 25 mg of the active substance:

Components:

^ -1-Phenyl-4-0X0-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -I * 3i8-triazaspiro (4,5) decane methanesulfonate hemihydrate 250 g milk sugar 1 956 g

Corn starch 90 S

Polyethylene glycol 6000 90 g

BATH ORIGINAL

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Talc powder 90 g

Magnesium stearate 24 g

Purified water q.s.

Procedure:

All powders are sieved with a sieve with a mesh size of 0.6 mm. The active ingredient is then mixed with lactose, talc, magnesium stearate and half of the starch in a suitable mixer. The other half of the starch is suspended in 45 ml of water and the suspension is added to the si'edenden solution of polyethylene glycol in 180 ml of water. The paste obtained is added to the powders and, if necessary, granulated with the addition of a further amount of water. The granulate is dried overnight at 35, driven through a sieve of 1.2 mm mesh size and pressed into tablets with a diameter of f _ß 1 mm, which have a breaking groove.

According to this and the preceding example, tablets are produced which contain 1 to 2 * 5 mg of a compound of the invention, e.g. one of the compounds mentioned in the examples.

209831/1 151

Example I9:

A solution of 5 g of 2-bromomethyl-5-acetyl-2,3-dihydro -benzofuran in 40 ml of 4-methyl-2-pentanone is under Stir to a mixture of 4.5 g of 1-phenyl-4-oxo-1, 3,8-triazaspiro (4.5) decane, 7 * 4 g. Sodium carbonate, 1 potassium iodide Crystal and 200 ml of 4-methyl-2-pentanone dropwise given. The reaction mixture is refluxed for 3 days, cooled and filtered. The precipitation will washed with 4-methyl-2-pentanone and water, the piltrate extracted with 5 # hydrochloric acid and the aqueous Solution made basic with ammonia. The mixture is extracted with chloroform, the extract is washed with water, dried, evaporated and the residue recrystallized from acetone •. The 1-phenyl-4-oxo ~ 8- (5-acetyl-2, 3-dihydro-2-benzofury! Methyl) -1,3 * 8-triazaspiro (4,5) decane, which melts at 166-168. The product is identical to that of Example 14.

The starting material is prepared as follows: A mixture of 50 g of 4-hydroxy-acetophenone, 44.5 g Allyl bromide, 51 * 5 potassium carbonate and 80 ml acetone are refluxed for 8 hours while stirring. The reaction mixture is left stand overnight at room temperature, dilute it with 500 ml of water and extract it with diethyl ether. The extract is washed with water, dried and concentrated

209831/1151

steams. The residue is distilled and the fraction boiling at 110 115 / 0.7 mm Hg is collected. The 4-allyloxy-acetophenone is obtained. The mixture is heated 57 g of this substance 90 minutes 230 ^0, allowed to cool and diluted with 80 ml acetic anhydride. The mixture is refluxed for 3 hours and evaporated. The residue is distilled and the fraction boiling at 122-128 ° / 0.2 mm Hg) is collected. 4-Acetyl-3-allyl-acetophenone is obtained.

A solution of 52.5 g of 4-acetyl-3-allyl-acetophenone in 180 ml of carbon disulfide at -5 to 0, dropwise, with 38 g of bromine, within 3 hours, added with stirring and the mixture evaporated under reduced pressure. The 1,2-dibromo-3- (2-acetoxy-5-acetyl-phenyl) -propane is obtained.

A mixture of 100 g of 1,2-dibromo-3- (2-acetoxy-5-

* acetyl-phenyl) -propane and 250 ml of diethyl ether is slowly with stirring, with a solution of 30 g of sodium methylate added in 500 ml of diethyl ether and the reaction mixture Boiled under reflux for 2 hours. The reaction mixture is cooled, filtered and the filtrate under reduced pressure Evaporated pressure. The residue is taken up in water, the mixture is extracted with methylene chloride and the extract washed with water, dried and evaporated. The return

209831/1151

stand is distilled and the at 155-157 ° / 0.07 mm Hg simmering fraction caught. The 2-bromomethyl-5-acetyl-2,3-dihydro-benzofuran is obtained.

Example 20:

A solution of 1.8 g of 1-phenyl-4-oxo-8- (5-acetyl-2,3-dihydro-2-benzofurylmethyl) -1,3 * 8-triazaspiro (4,5) decan in 500 ml of ethanol, 0.45 g of sodium borohydride is added in portions while stirring at 50. The reaction mixture is slowly evaporated under reduced pressure, the residue is triturated with water, filtered, washed with water and recrystallized from ethanol. The 1-phenyl-4-oxo-8- [5- (I-hydroxy- · ethyl) -2,3-dihydro-2-benzofurylmethyl] »1, 3j> 8-triazaspiro (4,5) decane of the formula

CH-CH

which melts at 196-200 °

209831/1151

Example 21:

Production of 10,000 capsules, each containing 10 mg of the active substance:

Components:

1-Phenyl-4-OXO-8- [5- (1-hydroxyethyl) -2,3-dihydro-2-benzofurylmethyl] -1, 3,8-triazaspiro (4,5) decan 100 g

Milk sugar 1,800 g

Talc powder 100 g

Procedure:

All powders are sieved with a sieve with a mesh size of 0.6 mm. The active ingredient is then first homogenized with the talc powder and then with the milk sugar in a suitable mixer. With a capsule filling machine capsules Nos. 3 ^w ith 200 mg of powder mixture filled.

Example 22:

A mixture of 1.97 g of £ -2- (d-10-camphorsulfonyl oxymethyl) -5-methoxy-2,3-dihydrobenzofuran, 20 ml of dimethyl formamide, 1.15 g l-phenyl-4-oxo-l, 3,8-triazaspiro (4,5) Dekane, 1.37 g of potassium carbonate and 3 potassium iodide crystals are refluxed for 15 minutes while stirring. That The reaction mixture is then concentrated under reduced pressure.

209831/1151

evaporated, the residue taken up in 100 ml of chloroform, the mixture washed twice with 50 ml of water, dried and evaporated. The residue is recrystallized from 25 ml of hot ethanol. The precipitate obtained after cooling is washed with .10 ml of cold ethanol. The 6-1-phenyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -1,3,8-triazaspiro (4,5) decane, which is 188-190 ⁰ melts. The product is identical to that of Examples 5 and I3.

The starting material is prepared as follows: A solution of 206.5 g of d, £ -2-bromomethyl-5-methoxy-2,3-dihydro-benzofuran and 105 g of benzoic acid in 300 ml of dimethylformamide is stirred, within of 14 minutes with a suspension of 138.2 g of potassium carbonate added in 500 ml of dimethylformamide. After 12 minutes the mixture is cooled, filtered and the residue washed twice with 100 ml of dimethylformamide. That The filtrate is concentrated and 500 g of ice are added, whereupon crystallization occurs. The precipitate obtained is filtered off, washed with water, taken up in 200 ml of diethyl ether, the solution with 100 ml of water, 5 # aqueous sodium bicarbonate solution and water washed, dried and evaporated. The residue will

2 0 9 8 31/1151

recrystallized from 800 ml of isopropanol and washed with 400 ml of ice-cold isopropanol. The d, β- 2-benzoyloxymethyl-5-methoxy-1,2-dihydro-benzofuran, which melts at 6 "J-68 , is obtained.

A solution of 43.8 g of potassium hydroxide in 500 ml of anhydrous ethanol is mixed with 150 gd, £ -2-benzoyloxymethyl-5-methoxy-2,3-dihydro-benzofuran and the mixture is refluxed for 75 minutes. During this time, the mixture is kept homogeneous by adding 10 ml of water each time. The reaction mixture is then evaporated under reduced pressure, the residue is taken up in 200 ml of water, the mixture is concentrated under reduced pressure and the concentrate is extracted 5 times with 300 ml of diethyl ether. The extract is dried and evaporated, the residue is distilled and the fraction boiling at 108-110 ° / 0.1 mm Hg is collected. The d, t -2-hydroxymethyl-5-methoxy-2,3-dihydro-benzofuran, which melts at 42-43, is obtained.

A solution of 39.08 g d, ß ^ - methoxy-2,3-dihydro-benzofuran in 350 ml of pyridine is under Stir with 56.13 g of d-10 camphorsulfonyl chloride within offset by 15 minutes. The temperature of the mixture is held between 18 and 20. The reaction mixture is kept at room temperature overnight and then under

209831/1151

evaporated under reduced pressure. The residue is extracted by shaking with a mixture of 600 ml of methylene chloride and 1370 ml of 4% ice-cold hydrochloric acid. The organic phase is separated off, washed with water, dried, filtered and evaporated. The residue is recrystallized from 875 ml of methanol and washed twice with 125 ml of methanol. The product is recrystallized again from 600 ml of boiling methanol, the precipitate obtained at room temperature is filtered off and washed twice with 125 ml of methanol. The C -2- (d-10 ^ camphorsulfonyloxymethyl) -5-methoxy-2,3-dihydro-benzofuran, which melts at 111-112 °, is obtained. [a3 _D = -205 ° (chloroform).

209831/1151

Claims (1)

Patent claims: •O" R ₄ wherein Ph is a 1,2-phenylene radical, each of the radicals R-, R ₂ and R, is hydrogen or lower alkyl, each of the radicals alk, and alkp is lower alkylene, which separates the nitrogen atom from the spiro carbon atom by 2 ring carbon atoms, R ^ stands for hydrogen, an aliphatic, araliphatic or aromatic radical, R, - stands for two hydrogen atoms, hydrogen and lower alkyl or oxo, and Rg stands for hydrogen, lower alkyl or lower hydroxyalkyl, their acyl derivatives, N-oxides, quaternary ammonium compounds and salts, thereby marked that one 209831/1151 a) Compounds of the general formulas III and IV ? 1 R,; ■ O i i. ι ^^ ^CHv \ / ^ ^CH \ / ^alk i \ _v CNR ₆ ^p h ^ C _v \ χ (in) and Ί ' C ^ ο alk _o 'N - C = R _r where X is a reactive esterified hydroxyl group or 'amino and Y is imino or two reactive esterified hydroxyl groups, only one of the radicals X and Y containing a nitrogen atom, or a metal salt of these ^λ amines or imines, condensed or b) Compounds of the general formulas V and VI Il JaIk ₁ C-NH- R ₆ Ph \ / ^N N ^X \> / (V) and aIk ζ ^ NH - Z = C = R ₅ (VI), where Z denotes oxo, hydrogen and amino or two reactive, functionally modified hydroxyl or amino groups, only one of the radicals Z and R ₅ containing an oxo group, condensed or 209831/1151 c) a dehydro and / or hydroxy derivative of a compound of the general formula VII (VII), where W is a free or reactive functionally converted group of the formula HO-C-R, means or represents the group of the formula -CH-R, if of at least one of the carbon atoms in the 2-position a double bond goes out, reduced, and, if desired, a compound obtained into another according to the invention Compound converts, or a obtained ™ compound into its salts, acyl derivatives, N-oxides or . Quaternary ammonium compounds converted, and / or, if desired, a salt obtained in the free compound. conversion converts, and / or, if desired, a mixture of isomers or racemates obtained into the individual Separates isomers or racemates, and / or, if desired, splits the racemates obtained into the optical antipodes. 209831/1151 2. The method according to claim 1, a), characterized in that that starting materials are used in which a reactive esterified hydroxyl group X or Y is a hydroxyl group esterified with a strong mineral acid or sulfonic acid. 3. Process according to one of claims 1, a) and 2, characterized in that starting materials are used, wherein X or Y is one with a hydrohalic acid, Sulfuric acid, methane, ethane, benzene or p-toluenesulphonic acid is esterified hydroxy group. 4.. 'Method according to claim 1, a) ,, characterized in that that the amines or imines mentioned are used in the form of their alkali metal salts. 5- The method according to any one of claims 1, a) to 4, characterized in that the implementation of the starting materials carried out in the presence of a basic condensing agent. 6. The method according to any one of claims 1, a) to 5 * characterized in that the reaction is carried out in the presence of alkali metal or alkaline earth metal carbonates, 209831/1151 BATH ORIGINAL hydroxides, lower alkanolates or of organic Performs nitrogen bases. 7. The method according to claim 1, b), characterized., that starting materials are used in which Z is two with a strong mineral acid or sulfonic acid means esterified hydroxyl groups. 8. The method according to any one of claims 1, b) and 7, characterized in that starting materials are used, wherein Z two with a hydrohalic acid, sulfuric acid, methane, ethane, benzene or p-toluenesulfonic acid means esterified hydroxyl groups. 9. The method according to claim 1, b), characterized in that starting materials are used in which Z is two means hydroxyl groups etherified with lower alkanols or glycols. 10. The method according to claim 1, b), characterized in that starting materials of the formula VI are used, where Z is two imidazolyl groups and R, - is oxo stands. 209831/1151 BAD ORIGINAt. ~ ⁶³ ~ 21B527B 11. The method according to claim 1, b), characterized in that the starting material of the formula VI is formamide used. 12. The method according to any one of claims 1, b), 7 and 8, characterized in that the reaction is carried out in the presence of a basic condensing agent. 13. The method according to any one of claims 1, b), 7 * 8 and 12, characterized in that the reaction in Presence of alkali metal or alkaline earth metal carbonates, hydroxides, lower alkanolates or organic nitrogen bases. 14. The method according to any one of claims 1, b) and 9, characterized in that acetals in claim 1, b) given formula VI used in the presence of acidic agents. 15. The method according to any one of claims 1, b), 9 and l4, characterized in that acetals are in the presence used by strong mineral acids or sulfonic acids. 209831/1151 16. The method according to one of claims .1, b), 9,] A and 15. » characterized in that one has the reaction carried out in the presence of a hydrohalic acid, sulfuric acid, methanoic, ethanoic, benzene or p-toluic acid. 17. The method according to claim 1, c), characterized in that the reduction with catalytically activated or nascent the hydrogen. 18. The method according to claim 1, c), characterized in that that the reduction is carried out with complex light metal hydrides. 19. The method according to any one of claims 1 to l8, characterized in that one obtained compound with a primary or secondary amino group, with a reactive ester of a corresponding alcohol implements. 20. The method according to any one of claims 1 to l8, characterized in that one obtained compound having a primary or secondary amino group by treatment with a reactive functional Acylated derivative of an acid. 209 831/1 151 '21. Process according to one of Claims 1 to 18, characterized in that an acyl derivative is obtained hydrolyzed by treatment with an acidic or basic hydrolyzing agent. 22. The method according to any one of claims 1 to 21, characterized in that one starts from a compound obtainable as an intermediate at any stage of the process, 'and undertakes the missing process steps, or forms a starting material under the reaction conditions or uses it in the form of a salt; 23. The method according to any one of claims 1 to 22 j, characterized in that maii compounds of the formula I shown in claim, wherein Ph is unsubstituted 1,2-phenylene or 1,2-phenylene substituted by at most 2 substituents selected from the group consisting of Lower alkyl, hydroxy, mercapto, lower alkoxy, lower alkylenedioxy, lower alkylthio, ilalogen, trifluoromethyl, nitro, amino, di-lower alkylamino, lower alkanoyl, lower alkylsulphinyl or lower alkylsulphonyl means, each of the symbols R ₁ , R ₂ and R ^ stands for hydrogen or lower alkyl, each of the Radicals alk, and alkp lower alkylene, which separates the nitrogen atom from the spiro carbon atom by two ring carbon atoms, means R ₁ , BAD ORJGIWAL 209831/1151 represents hydrogen, lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, cycloalkenyl-lower alkyl or H-Ph-C EL -, in which η denotes 0 to 4, Rf denotes two hydrogen atoms, hydrogen and lower alkyl or oxo and Rg is hydrogen, lower alkyl or hydroxy-lower alkyl group, a lower alkanoyl, lower alkanoyl or H-Ph-H-Ph-carbonyl derivative of these compounds in which Rj, and / or Rg is hydrogen, or Ph or Rg hydroxy, mercapto or contains amino, N-oxides or lower alkyl quaternary derivatives of these compounds in which R ^ and Rg are different from hydrogen and Ph is different from (amino) -1,2-phenylene, and their salts. 24. The method according to any one of claims 1 to 22, characterized in that compounds of the formula I shown in Ant- k ■ Spruch 1, wherein Ph 1,2-phenylene, (lower alkyl) -1,2-phenylene, (hydroxy) -1,2-phenylene, mono- or di- (lower alkoxy) -1,2-phenylene, (lower alkylenedioxy) -1,2-phenylene, (lower alkylthio) -1,2-phenylene, (halogen) -1,2- phenylene, (trifluoromethyl) -1,2-phenylene, (nitro) -1,2-phenylene, (amino) -1,2-phenyLeri, (di-lower alkylainino) -1,2 - phenylene, (MLederuikanoy L) - 1,2-phenylene, (mcderaLkylsiiirin / i) ~ L, 2-phtuiylon or- (NlederalkylfJLilfonyl) -1,2-phony'Liii bück, ucet, --———— ■ - 2 0 9 Q 1 I / i 1 5 1 BAD ORIGINAL each of the radicals R ₁ , R ₂ and R, stands for hydrogen or lower alkyl, each of the radicals alk., and alkp means lower alkylene, which separates the nitrogen atom from the spiro carbon atom by 2 ring carbon atoms, R ₂ , for hydrogen, lower alkyl, 3 to Cycloalkyl or cycloalkyl-lower alkyl containing 7 ring members or H-Ph-C Hp -, in which η is 0 to 4, Rp- is two hydrogen atoms, hydrogen and lower alkyl or oxo, and R, - is hydrogen, lower alkyl or hydroxy-lower alkyl means lower alkanoyl derivatives of these compounds in which R ₂ and / or Rg is hydrogen or Ph or Rg contains hydroxy, mercapto or amino, N-oxides or lower alkyl quaternary ammonium derivatives of these compounds in which R ₂ and Rg are hydrogen are different and Ph is different from (amino) -l, 2-phenylene, and produces their salts. 25. The method according to any one of claims 1 to 22, characterized characterized in that compounds of the general formula II (II), 20983 1/1151 wherein R _{7 is} hydrogen, lower alkyl, hydroxy, lower alkoxy, halogen or trifluoromethyl, each of the radicals Ro * R _Q and R _{11 is} hydrogen or lower alkyl, R _{10 is} lower alkyl, cycloalkyl containing 3 to 7 ring members or R _{7 is} phenyl, - and R _{12 is} hydrogen, lower alkyl, hydroxy-lower alkyl or lower alkanoyl, or lower alkyl quaternary ammonium derivatives of compounds in which R _{12 is} lower alkyl or hydroxy lower alkyl and prepares their salts. 26. The method according to any one of claims 1 to 22, characterized in that compounds of the formula II shown in claim 25, wherein R _{7 is} hydrogen, lower alkyl, hydroxy, lower alkoxy, halogen or trifluoromethyl, each of the radicals Rg, R _Q and R -, -, represents hydrogen or methyl, R _{10 represents} methyl, cyclohexyl or R ₇ -phenyl, and R _{12 represents} hydrogen, methyl, hydroxy P is methyl or acetyl, and prepares their salts. 27. The method according to any one of claims 1 'to 22, characterized in that compounds of the formula II shown in claim 25, wherein R _{7 is} hydrogen, methyl, methoxy, fluorine, chlorine or trifluoromethyl, each of the radicals Rg, R _g , R ₁₁ and R _{12 are} hydrogen, and R _{10 is} R ₇ -phenyl, and prepares their salts. 209831/1151 • 28. The method according to any one of claims 1 to 22, characterized. That 1-phenyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -1, 3,8- triazaspiro (4,5) dean or its salts. 29. The method according to any one of claims 1 to 28, characterized in that the process products are isolated in their optically left-handed form. 30. The method according to any one of claims 1, a) and 2, characterized in that starting materials are used in which a reactive esterified hydroxyl group is a hydroxyl group esterified with camphorsulfonic acid. 31. The method according to any one of claims 1 to 19, 29 and JO, characterized in that in a compound obtained which has a lower alkanoyl substituent on the 1,2-phenylene radical, this is converted to a corresponding (α-hydroxy-lower alkyl) substituent reduced. 32. The method according to claim Jl, characterized in that the reduction is carried out with a complex light metal hydride. 209831/1151 33 · The method according to any one of claims 1 to 22 and 30 to 32, characterized in that compounds of the formula I shown in claim 1, wherein Ph is substituted by unsubstituted 1,2-phenylene or 1,2-phenylene at most 2 substituents selected from the group consisting of lower alkyl, hydroxy, mercapto, lower alkoxy, Lower alkylenedioxy, lower alkylthio, halogen, lower (hydroxy, alkoxy, mono-, di- or trihalo) -alkyl, nitro, -amino, Di-lower alkylamino, lower alkanoyl, lower alkylsulfinyl or lower alkylsulfonyl, and the other symbols have the meanings given in claim 23 have, and their derivatives and salts mentioned in claim 23 produces. 34. The method according to any one of claims 1 to 22 and 30 to 32, characterized in that one compounds Il of the formula I shown in claim 1, wherein Ph is in claim 24 has given meaning and also stands for (lower a-hydroxyalkyl) -l, 2-phenylene, and the other symbols have the meanings given in claim 24 and their derivatives and salts mentioned in claim 24. 35. The method according to any one of claims 1 to 22 and 30 to 32, characterized in that one compounds 209831/1151 Formula II shown in claim 25, wherein R _{17 has} the meaning given in claim 25 and also represents lower α-hydroxy-alkyl and lower alkanoyl, and the other symbols have the meanings given in claim 25, and their derivatives mentioned in claim 25 and produces salts. 36. The method according to any one of claims 1 to 22 and 30 to 32., characterized in that compounds of the formula II shown in claim 25, wherein R _{17 is} hydrogen, alkyl, hydroxy, alkoxy, halogen, α-hydroxyalkyl, trifluorinethyl or alkanoyl means each of the remnants of Ro. " R _Q and R,., Represents hydrogen or methyl, R _{10 represents} methyl, cyclohexyl or R “-phenyl, R _{12 represents} hydrogen, methyl, hydroxymethyl or acetyl, where alkyl, alkoxy or alkanoyl contain at most 4 carbon atoms, and their Manufactures salts. 37. The method according to any one of claims 1 to 22 and 30 to 32, characterized in that compounds of the formula II shown in claim 25, wherein R _{7 is} hydrogen, · methyl, methoxy, fluorine, chlorine, 1-hydroxyethyl, trifluoromethyl or acetyl means that each of the radicals Rg, R ", R ₁₁ and R _{12 stands} for hydrogen or methyl, and R ₁₀ R _? -Phenyl, and its salts. 209831/1 151 38. The method according to any one of claims 1 to 22 and 3P * characterized in that 1-phenyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benzofury! methyl) -1,3,8-triazaspiro (4,5) decan or manufacture its salts. 39 · Process according to one of Claims 1 to 22 and 30 to 32, characterized in that 1-phenyl-4-oxo-8- [5- (l-hydroxy-ethyl) -2,3-dihydro-2-benzofurylfc methyl] -l, 3,8-triazaspiro (4,5) decane and its salts. 40. The method according to any one of claims 30 to 39. » characterized in that the process products are isolated in their optically left-handed form. 41. The method according to any one of claims 30 to 40, characterized in that one goes from one to any ) Process stage available as an intermediate compound goes out and carries out the missing procedural steps, or forms a starting material under the reaction conditions or is used in the form of a salt. 42. The method according to claim 1 for the preparation of new 8- (2,3-dihydrobenzofurylmethyl) -l, 3,8-triazaspiro (4,5) decans of the general formula II 209831/1151 (II), or R “is -phenyl, and wherein R is "hydrogen, lower alkyl, hydroxy, lower alkoxy," halogen or trxfluoromethyl, each of the radicals Ro, R _Q and R _{11 is} hydrogen or _{lower alkyl, R 10 is} lower alkyl, and cycloalkyl containing J5 to 7 ring members _{2 is} hydrogen, lower alkyl, hydroxy-lower alkyl or lower alkanoyl, lower alkyl quaternary derivatives of these compounds in which R _{12 is} lower alkyl or hydroxy lower alkyl, and their salts, characterized in that compounds of the general formulas IHa and IVa (HIa) and HN (IVa), wherein X is a reactive esterified hydroxy group, condensed or b) Compounds of the general formulas Va and VIa 20 9831/1151 BAD ORlQfNAL and R ₁₁ Y (Via) wherein Y is a group of the formula NHR ₁₂ (Va) ™ 10 HC = 0, HC (OCEL) ₂ or -CNH ₂ , R is hydrogen, _{0 is} R "-phenyl, condensed or c) Compounds of the general formula VIIa and (VIIa), ¹¹ LO wherein R _{10 is} lower alkyl or cycloalkyl having 3 to 7 ring carbon atoms, reduced and, if desired, converting a compound obtained into another compound according to the invention, or converting a compound obtained into its salts or lower alkyl quaternary ammonium derivatives, and / or » if if desired, converting a salt obtained into the free compound, and / or, if desired, separating a mixture of isomers obtained into the individual isomers. 209831/1151 BAD ORJGINAl. 43 «Method according to claim 42 a), characterized in that that the amines of the formula IVa are used in the form of their alkali metal salts. 44. The method according to claim te a), characterized in that that one uses starting materials in which X is esterified with a mineral or sulfonic acid Is hydroxyl group. .45 · Process according to one of claims 42, a) and 44, characterized in that starting materials are used, wherein X is one with a hydrohalic acid, sulfuric acid, methane, ethane, benzene or p-toluenesulfonic acid is esterified hydroxy group. 46. 'Method according to one of claims 42, a) to 45 * characterized in that the reaction is in Carries out the presence of a basic condensing agent. 47. The method according to any one of claims 42, a) to 46, characterized in that the reaction in the presence of alkali metal or alkaline earth metal carbonates, hydroxides or lower alkanolates or of organic nitrogen bases. 209831/1151 48. The method according to claim 42, b), characterized in that that starting materials of the formula Via, where Y is a group of the formula HC = 0 or H, used in the presence of acidic catalysts. 49 process according to claims 42, b) and 48, characterized in that the reaction is carried out in the presence of a mineral acid or organic sulfonic acid performs. 50. The method according to claim 49> characterized in that the reaction is carried out in the presence of hydrogen chloride, Sulfuric, methane, benzene or p-toluenesulphonic acid performs. 51. The method according to claim 42, c) characterized in that that the reduction is carried out with complex light metal hydrides. 52. The method according to any one of claims 42, c) and 51, characterized in that the reduction with Performs alkali metal aluminum hydrides or borohydrides. 2 0 9 8 3 1/115 1 53. The method according to any one of claims 42 to 52, characterized in that one obtained a compound with a secondary amino group, with a reactive Reacts ester of a corresponding alcohol. 54. The method according to any one of claims 42 to 52, characterized in that one obtained a compound having a secondary amino group, by reaction with . a reactive functional derivative of a corresponding Acid aylated. 55 · The method according to any one of claims 42 to 52, characterized in that one obtained acyl derivative by treatment with an acidic or basic hydrolyzing agent, hydrolyzed. 56. The method according to any one of claims 42 to 55 * characterized in that one of a compound obtainable as an intermediate at any stage of the process goes out and carries out the missing process steps, or a starting material under the reaction conditions forms or used in the form of a salt. 2 0 9 8 31/1151 BATH ORIGINAL 57 · The method according to any one of claims 42 to 56, characterized in that compounds of the formula II shown in claim 42, wherein R _{7 is} hydrogen, lower alkyl, hydroxy, lower alkoxy, halogen or trifluoromethyl, each of the radicals Rg, R and R. ,, represents hydrogen or methyl, R -._ represents methyl, cyclohexyl or R ₇ -phenyl, and R _{12 represents} hydrogen, methyl, hydroxymethyl or acetyl, and produces their salts. 58. The method according to any one of claims 42 to 56 *, characterized in that compounds of the formula shown in claim 42 TL _Λ wherein R _{7 is} hydrogen, methyl, methoxy, fluorine, chlorine or trifluoromethyl, each of the radicals Rg, R _Q , R -, -, and R ₁₂ stands for hydrogen, and RR _{7 stands for} -phenyl, and prepares their salts. * 59. ■ Method according to one of claims 42 to 56, characterized in that 1-phenyl-4-oxo-8- (5-methoxy ■ 2,3-dihydro-2-benzofurylmethyl) -1,3,8-triazaspiro (4,5) decan and makes its salts. 2 0 9 8 3 1/1151 BATH ORIGINAL -.79 - 60 * - The procedure described in Examples 1-4. 61. That described in Examples 5-16 and 19 Procedure. 62. The procedure described in Examples 20 and 22. 63. The according to the method of claims 1 to 62 obtained compounds. 64. 8- [1- (2,3-Dihydro-2-benzofuryl) alkyl] -1,3,8-triazaspiro (4,5) decane of the general formula I. I ¹ I ³ where Ph is a 1,2-phenylene radical, each of the radicals FL , R _? and R ^. is hydrogen or lower alkyl, each of the radicals alk, and alkp lower alkylene 209831/1151 means which separates the nitrogen atom from the spiro carbon atom by 2 ring carbon atoms, Ru stands for hydrogen, an aliphatic, araliphatic or aromatic radical, R ₁ - two hydrogen atoms, hydrogen and lower alkyl or oxo, and R, - for hydrogen, lower alkyl or lower hydroxyalkyl, their acyl derivatives, N-oxides and quaternary ammonium compounds w. 65 Compounds of the formula shown in Claim 64 I, where Ph is unsubstituted 1,2-phenylene or 1,2-phenylene substituted by a maximum of 2 substituents selected from the group consisting of lower alkyl, hydroxy, mercapto, lower alkoxy, Lower alkylenedioxy, lower alkylthio, halogen, lower (Hydroxy, alkoxy, mono-, di- or trihalo) -alkyl, nitro, "amino, di-lower alkylamino, lower alkanoyl, lower alkylsulphinyl or lower alkylsulphonyl means, each of the symbols R ₁ , Rp and R ₇ - stands for hydrogen or lower alkyl, each the radicals alk., and alk _? lower alkylene, which is the nitrogen atom from the spiro carbon atom through two ring carbon atoms 209831/1151 separates, means, R ₁ , for hydrogen, lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, cycloalkenyl-lower alkyl or H-Ph-C H "-, where η 0 means Ms 4, R ₁ - is two hydrogen atoms , Is hydrogen and lower alkyl or oxo, and R ^ is hydrogen, lower alkyl or hydroxy-lower alkyl, a lower alkanoyl, H-Ph-lower alkanoyl or H-Ph-carbonyl derivative of these compounds, in which R ^, and / or R, - denotes hydrogen or Ph or R, - hydroxy, mercapto or contains amino, N-oxides or lower alkyl quaternaries Derivatives of these compounds in which R ^, and R / ς are different from hydrogen and Ph from (amino) -1,2-phenylene is different. 66. Compounds of the formula I shown in claim 64, wherein Ph 1,2-phenylene, (lower alkyl) -1,2-phenylene, (hydroxy) -1,2-phenylene, mono- or di- (lower alkoxy) -1, 2-phenylene, (lower alkylenedioxy) -1,2-phenylene, (lower alkylthlo) -1,2-phenylene, (halogen) -1,2-phenylene, (lower a-hydroxyalkyl) -1,2-phenylene, (trifluoromethyl) -1,2-phenylene, (nitro) -1,2-phenylene, (amino) -1,2-phenylene, (di-lower alkylamino) -1,2-phenylene, (lower alkanoyl) -1,2-phenylene, ( Means lower alkylsulphinyl) -1,2-phenylene or (lower alkylsulphonyl) -1,2-phenylene, 209831/1151 BATH ORIGINAL each of the radicals "R ₁ , R _g and R-. represents hydrogen or lower alkyl, each of the radicals alk- and alkp represents lower alkylene, which separates the nitrogen atom from the spiro carbon atom by 2 ring carbon atoms, R _{2. represents} hydrogen, lower alkyl , Cycloalkyl or cycloalkyl-lower alkyl containing 3 to 7 ring members or H-Ph-C H _p -, in which η is 0 to 4, Rj- is two hydrogen atoms, hydrogen and lower alkyl or oxo, and R / - is hydrogen, lower alkyl or Hydroxy-lower alkyl denotes, lower alkanoyl derivatives of these compounds in which R _2. And / or R ^ denotes hydrogen or Ph or R, - contains hydroxy, mercapto or amino, N-oxides or lower alkyl quaternary ammonium derivatives of these compounds in which R ₂ , and R ^ - are different from hydrogen and Ph is different from (amino) -l, 2-phenylene. 67. Compounds of the general formula II 2 0 9 8 31/11 5.1 BATH ORIGINAL wherein R _{7 is} hydrogen, never alkyl, hydroxy, lower alkoxy, halogen, lower cc-hydroxy-alkyl, trifluoromethyl or lower alkanoyl; each of the radicals Rn, R _Q and R -, -. is hydrogen or lower alkyl, R, »is lower alkyl, cycloalkyl containing 3 to 7 ring members or R _{7 is} -Ptlenyl, and R, p is hydrogen, lower alkyl, hydroxy-lower alkyl or lower alkanoyl, or lower alkyl -qua ternary ammonium derivatives of compounds in which R _{12 is} lower alkyl or hydroxy-lower alkyl. 68. Compounds of the formula II shown in claim 67, wherein R _{7 is} hydrogen, alkyl, hydroxy, alkoxy, halogen, α-hydroxy-alkyl, trifluoromethyl or alkanoyl, each of the radicals Ro, R _Q and. R ,, stands for hydrogen or methyl, R, «means methyl, cyclohexyl or R ₇ -phenyl, R _,? stands for hydrogen, methyl, hydroxymethyl or acetyl, whereby alkyl, alkoxy or alkanoyl contain a maximum of 4 carbon atoms * 69 compounds of the formula II shown in claim 67, wherein R is hydrogen, methyl, methoxy, fluoro, chloro, 1-hydroxyethyl, trifluoromethyl or acetyl, each of the radicals Rg, R _g, R ₁₁ and R ₁₂ is hydrogen or methyl , and R ₁₀ is R -phenyl, 209831/1 151
BAO OBJGrNAi. 70. 1-Phenyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -1,3 * 8-triazaspiro (4,5) decan. 71. 1-Phenyl-4-oxo-8- (2,3-dihydro-2-benzofurylmethyl) -1.3 » 8-triazaspiro (4,5) decan. 72. 1-phenyl-4-oxo-8- (5-fluoro-2,3-dihydro-2-benzo ■ furylmethyl) -1,3 * 8-triazaspiro (4,5) decan. 73. l-Cyclohexyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -1,3j8-triazaspiro (4,5) decan. 74. 1-phenyl-4-oxo-8- (7-methoxy-2,3-dihydro-2-benzofurylmethyl) -1,3,8-triazaspiro (4,5) decan. 75. 1-phenyl-4-oxo-8- (4-methoxy-2,3-dihydro-2-benzofurylmethyl) l, 3,8-triazaspiro (4,5) decan. 76. 1-Phenyl-4-oxo-8- (6-methoxy-2,3-dihydro-2-benzofurylmethyl) -1,3,8-triazaspiro (4,5) decan. 77. 1-Phenyl-4-oxo-8- (5-methoxy-2-methyl-2,3-dihydro-2-benzofurylmethyl) -1,3,8-triazaspiro (4,5) decan. 209831/1151 BAD ORIGINAL 78. 4-0xo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl ) -1.3 * 8-triazaspiro (4.5) decan. 79-1-Phenyl-4-oxo-8- (5-acetyl-2,3-dihydro-2-benzofurylmethyl) -1,3,8-triazaspiro (4,5) decan. 80. 3-Methyl-2 _J 4-dioxo-8- (5-methoxy-2,3-dihydro-2 - "benz of urylmethyl) -1, 3,8-triazaspiro (4, 5) decan. 81. 1-Phenyl-4-oxo-8- [5- (1-hydroxy-ethyl) -2,3-dihydro-2-benzofurylmethyl] -1, 3,8-triazaspiro (4,5) decan. 82. 'Those mentioned in claims 64 to 8l Connections in their optically left-rotating form. 83. I -1-phenyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -1,3 * 8-triazaspiro (4,5) decan. 84. The compounds mentioned in claims 64 to 8l in their optical clockwise form. 85. d-1-Phenyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl-1,3,8-triazaspiro (4,5) decan. 209 831 / .1 151 86. Those mentioned in claims 64 to 85 Compounds in the form of their salts. 87. The compounds mentioned in claims 64 to 85 in the form of their therapeutically useful Salts. ^ 88. Methanesulfonate salts of djß- and £ -1-phenyl-4-oxo-8- (5-methoxy-2,3-dihydro-2-benzofurylmethyl) -1,3,8-triazaspiro (4j5) decan. 89 «Pharmaceutical products characterized by a content of one of the claims 64 to 85, and 88 compounds mentioned. 209831/1151